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OtherANALGESIA AND DRUGS OF ABUSE

DynorphinA-(2–17) Restores Spinal/Supraspinal Morphine Synergy in Morphine-Tolerant Mice

Li He and N. M. Lee
Journal of Pharmacology and Experimental Therapeutics March 1997, 280 (3) 1210-1214;
Li He
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Abstract

Morphine administered simultaneously to intracerebroventricular (i.c.v.) and intrathecal (i.t.) sites exhibits synergism, with the antinociceptive potency much greater than would be predicted from a simple addition of the potencies of the same dose administered to either site alone. This synergism was quantified in mice using both a fixed dose method, in which the morphine dose at one site was fixed while the AD50 (antinociceptive dose at 50% effectiveness) of morphine at the other site was determined; and a variable dose method, in which different doses of morphine were administered simultaneously to both sites at a fixed ratio, and the AD50 determined and compared to the AD50 at a single site alone. When animals were made tolerant to morphine by implantation of a 75-mg morphine pellet for 3 days, this synergism was eliminated, so that morphine administered simultaneously to i.c.v. and i.t. sites had an additive effect. However, administration of the peptide DynorphinA-(2–17) i.v. simultaneously to the test doses of morphine in morphine-tolerant animals resulted in a partial restoration of synergism. These results suggest that morphine-induced antinociception is highly dependent on an intact integrated central nervous system system and that the initial tolerance development is the result of a disruption of synergism between the central nervous system sites. Morphine tolerance results not from a reduced sensitivity to morphine at discrete central nervous system sites, but rather from a reduced synergistic interaction of morphine at spinal and supraspinal sites. In support of this conclusion, there was no tolerance observed in morphine-pelleted animals to morphine administered to i.c.v. or i.t. sites alone. DynorphinA-(2–17), a nonopioid peptide has previously been shown to enhance the antinociceptive potency of morphine in morphine-tolerant animals, appears to act by restoring this synergism.

Footnotes

  • Send reprint requests to: Dr. Nancy M. Lee, Geraldine Brush Cancer Research Institute, California Pacific Medical Center, Research Institute, 2330 Clay St., San Francisco, CA 94115.

  • ↵1 This work was supported by National Institute on Drug Abuse Grants DA-02643 and DA-10048.

  • Abbreviations:
    i.t.
    intrathecal
    i.c.v.
    intracerebroventricular
    dyn A
    dynorphin A
    NMDA
    N-methyl-D-aspartate
    AD50
    antinociceptive dose at 50% effectiveness
    • Received August 12, 1996.
    • Accepted November 15, 1996.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 280, Issue 3
1 Mar 1997
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OtherANALGESIA AND DRUGS OF ABUSE

DynorphinA-(2–17) Restores Spinal/Supraspinal Morphine Synergy in Morphine-Tolerant Mice

Li He and N. M. Lee
Journal of Pharmacology and Experimental Therapeutics March 1, 1997, 280 (3) 1210-1214;

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OtherANALGESIA AND DRUGS OF ABUSE

DynorphinA-(2–17) Restores Spinal/Supraspinal Morphine Synergy in Morphine-Tolerant Mice

Li He and N. M. Lee
Journal of Pharmacology and Experimental Therapeutics March 1, 1997, 280 (3) 1210-1214;
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